The Coagulation

Cascade
Ananya Mahesh, Sonal Churiwal, Rohan Pai
Mentor: Girish Pore, MD
Introduction

‒ When there is an injury to the blood vessels, the body eventually will
prevent the blood loss through a process known as the coagulation
cascade.
‒ The coagulation cascade is a multistep process which goes from the
formation of the clot after bleeding starts to the termination of the
clot and ends with breakdown of the clot.
‒ The coagulation cascade also explains the site of action of various
anticoagulants.
‒ Our presentation analyzes each step of this complex process.
Clot Formation
Steps of the Coagulation Cascade
PHASES OF THE HEMOSTATIC
PROCESS
– Endothelial injury and formation
of the platelet plug.
– Propagation of the clotting
process by the coagulation
cascade.
– Termination of clotting by
antithrombotic control
mechanisms.
– Removal of the clot by
fibrinolysis.
FORMATION OF THE PLATELET
PLUG
The functional response of activated
platelets involves four different
processes:
– Adhesion – The deposition of
platelets on the subendothelial
matrix
– Aggregation – Platelet-platelet
cohesion
– Secretion – The release of platelet
granule proteins
– Procoagulant activity – The
enhancement of thrombin
generation
Step 1 – Endothelial Injury

1. The endothelial cell wall lining blood vessel breaks open. The
body starts the process of the coagulation cascade and the next
step begins.
Step 2 – Formation of the Platelet Plug

2. Tiny platelets circulating body deposit in opening and form an

initial plug.
Step 3 - Propagation

3. Polymer fibrin strands act as a mesh over platelets to reinforce the

wall.
How Step 3 Happens

3A. Fibrinogen in the bloodstream doesn’t react or interact with each

other.
How Step 3 Happens

3B. Endothelial cells release proteins at the site of injury and blood
exposes new proteins to fibrinogen.
How Step 3 Happens
3C. New proteins eventually convert fibrinogen to fibrin, which in
turn becomes fibrin strands.
How Step 3 Happens

3D. These proteins call prothrombin.

The Cascade
Extrinsic pathway (workhorse, gets most of the coagulation process
done) is the “spark” to cascade.
It activates:
1. Tissue factor (Factor III, protein), which activates Factor VII.
The Cascade (cont.)

2. Factor VII activates Factor X (which works with V), finally activating
Factor II
3. Factor II, which is thrombin/prothrombin (which reactivates Factors
V, VII, VIII, XI, and XIII) then activates
4. Factor I, fibrinogen/fibrin, which become fibrin strands. Fibrin
strands get connected by
5. Factor XIII (which is activated by Factor II), which makes crosslinks
between strands, creating a mesh, plugging the blood cells.
The Cascade (cont.)

1. In the intrinsic pathway,

Factor XII activates Factor
XI
The Cascade (cont.)

2. Factor XI activates
Factor IX (which works
with Factor XIII), then
activating
3. Factor X (which works
with Factor II). The intrinsic
pathway continues until it
activates
The Cascade (cont.)

4. Factor II, just like the extrinsic pathway, and Factor II does the rest.
Additionally, Factor II starts up the intrinsic pathway by reactivating
some factors, after it is activated by the extrinsic pathway.
The Cascade (cont.)
The Termination of
the Clot
Ending of the Cascade
There are some negative feedback loops to prevent your body from
creating a bigger and bigger clot, due to how Factor II reactivates
the cascade.
It’s important for the cascade to terminate because if the clot
continues to form, it could risk blocking the flow of blood in the
body.
1. Arteries - conditions like strokes, heart attacks etc.
2. Veins - Deep vein thrombosis
3. Capillaries - e.g. conditions when people get chemotherapy
Termination of the Clot

Once a clot forms, the clotting process is terminated to prevent the clot
from obstructing blood flow.
Natural anticoagulants are produced to stop the clotting process.
– Tissue Factor Pathway Inhibitors
– Protein C
– Protein S
– Antithrombin
Tissue Factor Pathway Inhibitor (TFPI)

‒ Natural Anticoagulant secreted by the endothelium

‒ Single chain polypeptide
‒ Inhibits Factor Xa, which is one of the most important factors in
forming a clot
Protein C and S

‒ Both are Vitamin K dependent glycoproteins

‒ Protein C activates Protein S
Antithrombin

‒ Natural anticoagulant
‒ Inhibits the activity of thrombin, which causes clotting
‒ Thrombin stimulates the production of antithrombin, which
decreases the production of thrombin from prothrombin.
‒ Antithrombin also stops the activation of Factor X.
Removal of Clot by
Fibrinolysis
What is Fibrinolysis?

Fibrinolysis remodels and degrades fibrin-rich thrombus with a

tightly regulated process.
Purpose of Fibrinolysis

‒ Restores normal blood flow to the area of injury by dissolving a

stable fibrin clot
‒ Converts plasminogen to plasmin
‒ Failure to complete fibrinolysis may contribute to development of
a thrombus.
Steps of Fibrinolysis

‒ After the clot has been formed and the tissue repaired,
fibrinolysis is activated through the attraction of plasminogen and
tissue plasminogen activator (t-PA) to the lysine residues of fibrin.
Steps of Fibrinolysis (cont.)

‒ The t-PA catalyzes the conversion of plasminogen to plasmin.

‒ Plasmin digests the fibrin clot and yields fibrin degradation
products.
‒ After the clot lysis is finished, the antiplasmin inactivates the
plasmin once it enters the circulation.
Reactions that Counteract Fibrinolysis

All of these reactions promote fibrin stability:

1. Factor XIIIa → cross-links fibrin
2. Thrombin-activatable fibrinolysis inhibitor → removes lysine
residues from fibrin
3. Plasminogen activator inhibitor type 1 (PAI-1) → inactivates t-PA
4. Α2-antiplasmin → inactivates plasmin
Primary Fibrinolysis

Primary Fibrinolysis
– Rapid clot breakdown because of excess t-PA
– Objective is to treat excessive plasmin activity
• Antifibrinolytic agent is a common course of treatment
Secondary Fibrinolysis
Secondary Fibrinolysis:
– Result of hypercoagulability
• increased breakdown of clots due to larger number of clots
being formed
• Reasons:
A) Acquired
B) Genetic
– Treatment = anticoagulant therapy
Application of Secondary Fibrinolysis

‒ Stroke is a very common and a very dangerous situation.

‒ It can happen due to many reasons but a blood clot is one of the
most common causes.
‒ These changes happen suddenly without a warning and can
cause long term disability or even death.
‒ Breaking the clot down in 6 hours or less is critical to save a
patient’s life, permanent damage and long term disability.
‒ t-PA is used on an emergency basis in every ER to save a stroke.
Summary and Conclusions

‒ The coagulation cascade is a crucial process because it prevents

excess blood loss by making a clot in the blood vessels and
terminating it, finally removing it once the walls have healed.
‒ There are many dangerous implications if any step of the
coagulation cascade if there is any interference that prevents a
step from happening.
‒ Coagulation cascade also gives an idea of where the various
anticoagulants act, which helps in the synthesis of newer
anticoagulant agents and their antagonists.
Acknowledgements

We would like to thank:

‒ Dr. Girish Pore for his expert help throughout the project.
‒ Dr. Atul Laddu and Mrs. Jayashree Laddu for their help and
support throughout the presentation.
‒ Ms. Archana Athalye and Ms. Supriya Sawant for their
organization throughout the project.
‒ GTF for providing us a platform for this presentation.
‒ Our parents for their encouragement throughout the process.
References

https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4260295/
https://www.khanacademy.org/science/health-and-medicine/advance
d-hematologic-system/hematologic-system-introduction/v/coagulatio
n-cascade
https://www.thrombosisadviser.com/the-coagulation-cascade/
https://www.youtube.com/watch?v=LVYmV5mK6QI
https://www.youtube.com/watch?v=9xdOqpWTITE